Intermediates in the preparation of 3beta-hydroxy-20-oxo-5alpha-pregnane



United States Patent 3,190,879 INTERMEDIATES IN THE PREPARATION OF 35-HYDROXY-ZO-0XU-5oz-PREGNANE Wataru Nagata, Nishinomiya-slii, Hyogo,Tadao Terasawa, Taitatsuki-shi, Osaka, and Tsutomn Aoki, Amagasairi-shi,Hyogo, .i'apan, assignors to Shionogi 8; Co., Ltd., Osaka, .lapan v v NoDrawing. Filed Mar. 13, 1964, Ser. No. 351,838 Claims priority,application Japan, Mar. 14, 1963, 38/14,297, 38/ 14,298, 38/1 1,299 8Claims. (Cl. 260-23955) The present invention relates to total synthesisof steroid, and particularly to a process for synthesizing 3(3-hydroxy-ZO-oxo-Sa-pregnane which is applicable in industry.

Although there have been reported a number of totally synthetic methodsof preparing steroids, most of them give the objective steroids only invery low yields and can not be practically adopted in industry.

There has been now completed a totally synthetic method of preparing3B-hydroxy-ZO-oX0-5a-pregnane in which the total yield of the saidcompound is so high that it makes it possible to actually adopt theprocess in industry.

Accordingly, a basic object of the present invention is to provide atotally synthetic method of preparing 3(3- hydroxy-ZO-oxo-Swpregnane.Another object of this invention is to provide an industriallyapplicable process for preparing 3,B-hytlroXy-20-oxo-5cz-pregnane. Afurther object of the invention is to provide a process for preparingintermediates in the total synthesis of 3,6-hydroxy- ZO-oxo-Sa-pregnanein good yields. These and other objects will be apparent to thoseconversant with'the art to which the present invention pertains from thesubsequent description.

The process of the present invention can be illustrated by the followingscheme:

OCH3

OCH;

H it

(VIII) (IX) ON ON on, CH3 0 47:0 (2 :l l o n H /;\i/

Ll s

I-IO- 1 oH=Nn 0110 0113 0 CH3 0 t t \O Qj] /;\i /;\i/

( I (XIII) CH3 CH3 on on 3 0 0:0

H- H /;\i/ /;\l/

HO 5 HO- 5 (XIV) (XV) wherein acyl represents an acyl group such aslower alkanoyl (e.g. acetyl, propionyl, butyryl), benzoyl and loweralkylbenzoyl (e.g. t-oluoyl, xyloyl).

The starting material of the present invention is a known compound, i.e.2,3,4,9,l0,l2,8-hexahydro-7-methoxy-12fi-methyl-2-oxophenanthrene[Howell et al.: J. Chem. Soc., p. 1248 (1958)].

According to the present invention, the starting 2,3,4,9,l0,l2fihexahydro 7 methoXy 12B methyl-2- oxophenanthrene (I) is first subjectedto reduction. The reduction may be carried out by treating2,3,49,10,125-

hexahydr-o-7-methoxyl=2,8-methyl-2-oxophenanthrene (I) with metalliclithium in liquid ammonia in the presence of a lower alkanol (e.g.methanol, ethanol, pro-panel), usually at a relatively low temperature(e.g. to C.). Sometimes a co-solvent such as ether, dioxane andtetrahydro-furan may be used as the reaction solvent. A considerableexcess amount of metallic lithium, usually from about 50 to about molesto one mole of the starting2,3,4,9,10,12/3-hexahydro-7-methoxy-1Zfl-methyl- 2-oxophenanthrene (I),should be used for obtaining a 3 favorably high yield of the product,is. 1,2,3,4,5,8,9,l0, 1la,12,8-decahydro2/3-hydroxy7-methoxy 125methylphenanthrene (II).

The 1,2,3,4,5,8,9,10,1 c,12p-dBCZlllYCllO-Zfi-llYdl'OXY-7-methoxy-12/3-methylphenanthrene (I1) is then subjected to hydrolysis.The hydrolysis may be carried out by treatingl,2,3,4,5,8,9,10,1la,1Zfi-decahydro-2/3-hydroxy-7-methoxy-IZfl-methylphenanthrene (II) with an acid such as an inorganicacid (e.g. hydrochloric acid, sulfuric acid) and an organic acid (e.g.acetic acid, oxalic acid) at a temperature from about 10 to about 100C., usually while heating on a water bath. In the hydrolysis, awater-miscible organic solvent such as methanol, ethanol andtetrahydrofuran may be used for effecting the reaction smoothly,

The resultant 1,2,3,4,5,6,7,9,10,lloc,l2fl,l3x-dodecahydro-2,8-hydroxy-l2fl-methyl-74oxophenanthrene (III) is thensubjected to acylation. The acylation may be executed by treating1,2,3,4,5,6,7,9,10,llot,l2fl,13ucdodecahydro-ZB-hydroxy 12B methyl 7oxophenanthrene (III) with an organic acid anhydride (e.g. aceticanhydride, propionic anhydride, benzoic anhydride) or an organic acidhalide (e.g. acetyl chloride, propionyl chloride, benzoyl chloride) inthe presence of an organic base (e.g. pyridine, picoline,trimethylamine) at a temperature from room temperature (10 to 30 C.) torefluxing temperature.

The resulting 1,2,3,4,5,6,7,9,10,l1a,12[3,13a-dOd6Cahydro-Zfl-acyloxy-l2,8-methyl-7-oxophenanthrene (IV) is then subjectedto condensation with 1-halogeno-4-oxopentane ethyleneketal. Thus, thecondensation may be effected by treating1,2,3,4,5,6,7,9,10,11a,l2/3,l3a-dodecahydro-2,8-acyloxy-l2/3-methyl 7oxophenanthrene (IV) with l-halogeno-4-oxopentane ethyleneketal in thepresence of an alkali metal hydride (e.g. sodium hydride, potassiumhydride) or an alkali metal amide (e.g. sodium amide, potasium amide) inan inert organic solvent (e.g. benzene, toluene, xylene), usually arounda boiling temperature of the mixture. In general, the reaction ispreferred to be carried out in an inert gas such as nitrogen.

Then, the resultant 1,2,3,4,5,6,7,9,10,11a12{3,13adodecahydro 2,8acyloxy-S-(4,4-ethylenedioxypentyl)- 12/3-methyl-7-oxophenanthrene (V)is subjected to hydrolysis. The hydrolysis may be carried out bytreating 1,2,3,4,5,6,7,9,10,11a-12fi,13u-dodecahydro 2,8 acyloxy-8-(4,4-ethylenedioxypentyl)-l2/3-methyl 7 oxophenanthrene (V) with analkali (e.g. sodium hydroxide, sodium carbonate, potassium carbonate) inan aqueous lower alkanol (e.g. methanol, ethanol), usually whilerefluxing.

The resulting 1,2,3,4,5,6,7,9,10,1la-12fi,l3adOdCCa hydro 2 8 hydroxy 8(4,4-ethylenedioxypentyl)425- methyl-7-oxophenanthrene (VI) is thensubjected to reduction. The reduction may be executed by treating1,2,3,4,5,6,7,9,10,1n n 2,13 dodecahydro-2/3-hydroxy-8-(4,4-ethylenedioxypentyl)-12fi-methyl 7 oxophenanthrene (V1) with analkali metal (e.g. lithium, sodium) or an alkaline earth metal (e.g.calcium) in liquid ammonia at a relatively low temperature (e.g. 70 to-80 C.), followed by treatment of the reaction mixture with a suitableproton source (e.g. ammonium chloride). In order to carry out thereaction smoothly, there may be used a suitable co-solvent (e.g. ether,dioxane, tetrahydrofuran) The thus-preparedl,2,3,4,5,6,7,8,9,10,l-loc,12B,130:,145- tetradecahydro 2p hydroxy Sfl(4,4 ethylenedioxypentyl)-lZfi-methyl-7-oxophenanthrene (VII) is thensubjected to deketalation. The deketalation may be effected by treating1,2,3,4,5,6,7,8,9,l0,l1a,12B,13a,14fi-tetradecahydro-Zfl-hydroxy-ttfi-(4,4 ethylenedioxypentyl) 112pmethyl-7-oxophenanthrene (VII) with an organic acid (e.g. acetic acid,p-toluenesulfonic acid) or an inorganic acid (e.g. hydrochloric acid,sulfuric acid), usually in an aqueous medium, at a temperature from roomtemperature (e.g. 10 to 30 C.) to refluxing temperature.

Then, the resulting 1,2,3,4,5,6,7,8,9,l0,1la,12p,13a,14,3-tetradecahydro-Zfl-hydroxy-Sfi-(4 oxopentyl) 12 8-methyl-7-oxophenanthrene (VIII) is subjected to cyclization. Thecyclization may be carried out by treating1,2,3,4,5,6,7,8,9,10,1la,125,l3a,14fl-tretradecahydro 2B- hydroxy-8B-(4oxopentyl) '12fl-methyl 7 oxophenanthrene (VIII) with an alkalihydroxide (e.g. sodium hydroxide, potassium hydroxide) in a loweralkandl (e.g. methanol, ethanol, propanol) diluted with water. For thesuccessful accomplishment of the cyclization, the use of a mixture of alower alkanol and water is indispensable. The mixing ratio of a loweralkanol to Water depends on the kind of the used lower alkanol, and sucha high dilution as 1 to 5-20 by weight is generally preferred. Thereaction can proceed within a range of temperature from about 50 toabout C.

The thus-obtained 3/3 hydroxy 20-oxo-18-nor-5a-13- (17 )-pregnene (IX)is further subjected to angular cyanation. The angular cyanation ispreferred to be effected according to the method described and claimedin the copending application of W. Nagata, Serial No. 261,215, filedFebruary 26, 1963. Thus, the object can be attained by treating 3,6hydroxy 20-oxo-18-nor-5a-13(17)-pregnene (IX) with a complex anionrepresented by the formula:

wherein R represents a lower alkyl group (e.g. methyl, ethyl, propyl,butyl) or a lower alkoxy group (e.g. methoxy, ethoxy, propoxy, butoxy)and R and R each represents a lower alkyl group (e.g. methyl, ethyl,propyl, butyl), a lower alkoxy group (e.g. methoxy, ethoxy, propoxy,butoxy), a halogen atom (e.g. chlorine, bromine) or a cyano group in asubstantially anhydrous medium, followed by treatment with an alkali inan aqueous medium. The said complex anion can be produced, for instance,by treating an aluminum compound represented by the formula:

AlRRR wherein R, R and R each has the same significance as designatedabove with hydrocyanic acid in a substantially anhydrous medium ortreating the aluminum compound with an aluminum cyanide compoundrepresented by the formula:

AlRR'CN wherein R and R each has the same significance as designatedabove in a substantially anhydrous medium, the aluminum cyanide compoundbeing prepared by treating an aluminum hydride compound represented bythe formula:

AlRRH wherein R and R each has the same significance as designated abovewith hydrocyanic acid in a substantially anhydrous medium. As thereaction medium, there may be employed an inert non-polar solvent suchas benzene, ether, tetrahydrofuran and dioxane. The reaction can proceedat a temperature from room temperature (10 to 30 C.) to refluxtemperature, preferably around room temperature.

The resultant 3,8 hydroxy 20 oxo Sa-pregnane-IS- nitrile (X) is thensubjected to ketalation. The ketalation may be executed by treating3e-hydroxy-20-oxo-5upregnane-lS-nitrile (X) with ethyleneglycol in thepresence of an acid such as p-toluenesulfonic acid and sulfuric acid,usually while refluxing.

The thus-prepared 3fi-hydroxy-ZQZO-ethylenedioxy-5apregnane-18-nitrile(XI) is then subjected to reduction. The reduction may be effected bytreating Bis-hydroxy- 20,20-ethylenedioxy-Sa-pregnane-lS-nitrile (XI)with a hydrogenated metal complex such as lithium aluminum hydride,sodium aluminum hydride, magnesium aluminum hydride, aluminum hydride,lithium aluminum and alkoxy hydride in an inert organic solvent (e.g.ether, dioxane, tetrahydrofuran) at a temperature from room temperature(10 to 30 C.) to refluxing temperature.

The resultant 3e hydroxy 18 imino-20,20-ethylenediOXy-Sa-pregnane (XII)is further subjected to partial hydrolysis. The hydrolysis may becarried out by treating 3,8 hydroxy18-imino-20,ZO-ethylenedioxy-Sa-pregname with an acid or a base in asuitable solvent (e.g. methanol, ethanol). The use of a buffer solutionof acetic acid and sodium acetate is preferred. The reaction is usuallyperformed while refluxing.

The resulting 3fi-hydroxy-ZOZO-ethylenedioxy-Sa-pregnan-lS-al (XIII) isthen subjected to reduction. The reduction may be realized by a per seconventional procedure, i.e. so-called Woltf-Kishner reduction or Huang-Minlon reduction. Thus, 3,B-hydroxy 20,20 ethylenedioxy-5a-pregnan-18-al(XIII) is treated with an alkali hydroxide (e.g. potassium hydroxide),hydrazine hydrate and a lower :alkyleneglycol (e.g. diethyleneglycol,tr'iethyleneglycol), followed by decomposition of the resultant productwith water to give 3B-hydroxy-2(),20-ethylenediOXy-Se-pregnane (XIV).

Finally, the thus-prepared 3fl-hydroxy-20,20-ethylenedioxy-5u-pregnane(XIV) is subjected to deketalation. The deketalation can be accomplishedby a per se conventional procedure, i.e. treatment with an acid (e.g.acetic acid, hydrochloric acid, sulfuric acid) in an aqueous mediumordinarily while refluxing.

Although the process of the present invention is hereinbeforeillustrated step by step, some of these steps may be executedsuccessively without purification of the product in each step.

The finally produced 35 hydroxy 20-oxo-5ot-pregnane (XV) is a knowncompound and can be converted into various physiologically activesteroids by conventional methods.

Presently-preferred embodiments of the present invention are shown inthe following examples.

Example 1 0 CH3 OCHa To a solution of metallic lithium (28 g.) in liquidammonia (1800 ml.), there is added dropwise a solution of2,3,4,9,10,12(3-hexahydro-7-methoxy-1ZB-methyl-Z-oxophenanthrene (1 1g.) in a mixture of anhydrous dioxane (70. ml.) anhydrous ethanol (110ml.) and anhydrous ether (370 ml.) in 1 hour at 70 to -80 C. whilestirring. Stirring is further continued for 1-5 minutes. Anhydrousethanol (660 ml.) is dropwise added to the resultant mixture until theblue colour disappears. Then, the ammonia is evaporated at roomtemperature to 30 C.). The resultant mixture is combined with a largeamount of water and shaken with a mixture of chloroform and ether (1:3).The organic solvent layer is washed with saturated sodium chloridesolution, dried over anhydrous sodium sulfate and the solvent evaporatedunder reduced pressure. The residue is crystallized from a mixture ofacetone and ether to give 1,2,3,4,5,8,9,10,1101,12 decahydro 213 hydroxy7-methoxy-1Zfi-methylphenanthrene (8.35 g.) as crystals melting at 132to 135 C. Yield, 74.1%.

Example 2 To a solution of 1,2,'3,4,5, 8,9,1O,110:,1213-4166311Yd10-2B-hydroxy-7-methoxy-12e-methylphenanthrene (500 mg.) in methanol (30rnl.), there is added 4 N hydrochloric acid ('8 ml.), and the resultantmixture is refluxed on a Water bath for 20 minutes. The reaction mixtureis concentrated under reduced pressure, combined with a large amount ofwater and shaken with ether. The ether layer is washed with 2 N sodiumcarbonate solution and water in order, dried over anhydrous sodiumsulfate and the solvent evaporated under reduced pressure. The oilyresidue (362 mg.) is crystallized from a mixture of acetone and ether togive l,2,3,4,5,6,7,9,10, 11d,12fi,13OL-dO- decahy-dro 2e hydroxy12fl-methyl-7-oxophenanthrene (314 mg.) as crystals melting at12l to 123C. Yield, 6 6.7%.

Example 3 To a solution of 1,2,3,4,5,6,7,9,10,11a,12B-13oc-d0- decahydroZfi hydroxy 12p-methyl-7-oxophenanthrene (1.74 g.) in anhydrous pyridine(12 ml.), there is added benzoyl chloride (2g) while cooling with ice,and the resultant mixture is stirred for a while and then allowed tostand at room temperature (10 to 30 C.) overnight. The reaction mixtureis combined with water and shaken with chloroform. The chloroform layeris washed with dilute sulfuric acid, water, sodium carbonate solutionand water in turn, dried over anhydrous sodium sulfate and the solventevaporated under reduced pressure. The residue (3.2 g.) is crystallizedfrom a mixture of acetone and etherto give1,2,3,4,5,6,7,9,1'0,11a,12B,=13e-dodecahydno- ZB-benzoyloxy-lZfl-methyl-7-oxophenanthrene (2.19 g.) as crystals melting at178.5 to 179.5 C. Yield, 87.3%.

tion of1,2,3,4,5,8,9,10,1la,12B-deCahydro-ZB-hydroxyfimethoxy-lZfi-methylphenanthrene(40 g.) in methanol (2000 ml.) while refluxing'on a water bath, and theresultant mixture is refluxed for 15 minutes. The reaction mixture isconcentrated under reduced pressure and poured onto a mixture of ice andwater. The resultant mixture is shaken with chloroform. The chloroformlayer is washed with 2 N sodium carbonate solution and water in order,dried over anhydrous sodium sulfate and the solvent evaporated. Theresultant crude l,2,3,4,5,6,7,9,10,

lloc,l2,8,l3oa dodecahydro 2,8 hydrxy-12fl-methyl-7- oxophenanthrene(43.73 g.) is dissolved in anhydrous pyridine (20 ml.), combined withbenzoyl chloride (33.8 g.) and the resultant mixture allowed to stand atroom temperature (10 to 30 C.) overnight. The reaction mixture iscombined with water and shaken with chloroform. The chloroform layer iswashed with dilute sulfuric acid, water, sodium carbonate solution andWater in turn, dried over anhydrous sodium sulfate and the solventevaporated under reduced pressure. The residue (67.8 g.) is crystallizedfrom a mixture of chloroform, acetone and ether to give1,2,3,4,5,6,7,9,10,1104,125,130:-dodecahydro-2fibenzoyloxy-l2fi-methyl-7-oxophenanthrene(48.62 g.) as crystals melting at 178.5 to 179.5 C. Yield, 89.4%.

Example 5 Example 6 A solution of1,2,3,4,5,6,7,9,10,1la,12,8,13a-dodecahydro 2,8 benzoyloxy 12,8 methyl 7oxophenanthrene (42.5 g.) in anhydrous xylene (1200 ml.) is heated todistill off 150 millilitres of xylene. After cooling to room temperature(10 to C.) sodium hydride (4.66 g.) is added thereto, and the resultantmixture is refluxed for 1 hour in nitrogen stream. Then,a solution ofl-bromo- 4-oxopentane ethyleneketal (29 g.) in anhydrous xylene (360ml.) is dropwise added thereto, and the resultant mixture is refluxedfor 3 hours. The reaction mixture is poured onto a mixture of ice andwater (180 ml.). The organic solvent layer is washed with water, driedover anhydrous sodium sulfate and the solvent evaporated under reducedpressure to give 1,2,3,4,5,6,7,9,10,110:,125,-

13cc dodecahydro 2B benzoyloxy 8 (4,4ethylenedioxypentyl)-1Zp-methyl-7-oxophenanthrene (57.3 g.) as an oil.

o in Example 7 To a solution of1,2,3,4,5,6,7,9,l0,11a,12fl,13a-dodecahydro 2 8 benzoyloxy 8 (4,4ethylenedioxypentyl)- 12fi-methyl-7-oxophenanthrene (57.3 g.) inmethanol (1900 ml.), there is added a solution of sodium carbonate (53g.) in a mixture of methanol (440 ml.) and water (660 ml.), and theresultant mixture is refluxed for 2 hours on a water bath. The reactionmixture is concentrated under reduced pressure, combined with a mixtureof ice and water and shaken with ether. The ether layer is washed withwater, dried over anhydrous sodium sulfate and the solvent evaporated togive 1,2,3,4,5,6,7,9,10,lla, 125,130;dodecahydro-2fl-hydroxy-8-(4,4-ethylenedioxypelntyl)-12,8-rnethyl-7-oxophenanthrene(44.07 g.) as an or Example 8 Into a solution of metallic lithium (16g.) in liquid ammonia (3600 ml), there is dropwise added a solution of1,2,3,4,5,6,7,8,9,10,11m,12B,13ot-dodecahydro-Zfl-hydroxy-8-(4,4-ethylenedioxypentyl)dQfl-methyl 7 oxophenanthrene-(44.07 g.) inanhydrous ether (1400 ml.) in 1 hour while cooling at to C. and theresultant mixture is stirred for 5 minutes. Then, ammonium chloride (107g.) is portionwise added to the reaction mixture whereby the blue colourdisappears. After evaporation of liquid ammonia, the residue is combinedwith water and shaken with ether. The ether layer is washed with sodiumchloride solution, dried over anhydrous sodium sulfate and the solventevaporated under reduced pressure to givel,2,3,4,5,6,7,8,9,l0,1loc,12fi,l3oc,l4/3 tetradecahydro-2,8-hydr0xy-8B(4,4-ethylenedioxypentyl)-12B-methyl-7-oxophenanthrene (42.29 g.) as anoil.

Example 9 1,2,3,4,'5,6,7,8,9,l0, 1'1a,125,1-30:14p-tetradecahydro2flhydroxy-Sfi- (4-ox-opentyl) -12,8-rnethyl-7-oxophenanthrene (37.06g.) as an oil.

Example 10 A solution of1,2,3,4,5,6,7,8,9,10,11a,12,8,l3u,14,8-tetradecahydro 2,8hydroxy-8B-(4-oxopentyl)-12,8-methyl-7- oxophenanthrene (17 g.) inethanol (100 ml.) is combined with water (1000 ml.) and heated at 85 C.while stirring in nitrogen stream. A mixture of N sodium hydroxidesolution (20 ml.) and ethanol ml.) is dropwise added thereto in 15minutes. The resultant mixture is stirred at the same temperature for 7hours during which a crystalline product is precipitated. The reactionmixture is cooled and filtered. I

The collected substance is dissolved in chloroform, washed with water,dried over anhydrous sodium sulfate and the solvent evaporated underreduced pressure. The resultant oil (12.7 g.) is crystallized from etherto give 3fl-hydroxy-20-oxol8-nor-5a-13(17)-pregnene (6.84 g.) ascrystals melting at 156 to 157 C.

The filtrate is shaken with ether. The ether layer is combined with themother liquor of the above crystallization, washed with water, driedover anhydrous sodium sulfate and the solvent evaporated under reducedpressure. The residue (9.07 g.) is dissolved in ethanol (53 ml.) anddiluted with water (530 ml.). The resultant mixture is combined with amixture of N sodium hydroxide solution (10.6 ml.) and ethanol (15.9 ml.)and heated at C. for 3.5 hours while stirring in nitrogen stream. Aftercooling, the separated substance is collected by filtration, dissolvedin chloroform, washed with water, dried over anhydrous sodium sulfateand the solvent evaporated under reduced pressure. The resultant oil iscrystallized from ether to give additional crystals (1.49 g.) of3,8-hydroxy-20-oxo-18-nor-5e-13(17)-preg- To a solution of triethylaluminum (5.70 g.) in anhydrous tetrahydrofuran (30 ml.), there is addeda solution of hydrogen cyanide (0.81 g.) in anhydrous tetrahydrofuran(10 ml.) while cooling. The resultant solution is added to a solution of35-hydroxy-20-oxo-1S-nor-Sal3(l7)-pregnene (3.02 g.) in anhydroustetrahydrofuran (30 ml.) While cooling at 0 C. and the resultant mixtureis allowed to stand at room temperature (10 to 30 C.) for 1.5 hours in aflask with a stopper. The reaction mixture is poured onto 2 N sodiumhydroxide solution while cooling and shaken with chloroform. Thechloroform extract is washed with 2 N sodium hydroxide solution andwater in turn, dried over anhydrous sodium sulfate and the solventevaporated under reduced pressure. The crystalline residue (3.52 g.) iscrystallized from a mixture of acetone and ether to give3B-hydroxy-20-oxo 5a-pregnane-18-nitrile (2.55 g.) as crystals meltingat to 168 C.

Example 12 To a solution of 3fi-hydroxy-20-oxo-5u-pregnane-l8- nitrile(3 g.) in anhydrous benzene (30 ml.), there is added ethyleneglycol(2.28 g.) and p-toluenesulfonic acid mg), and the resultant mixture isheated in order to distill off an azeotropic mixture of the eliminatedwater and the benzene. Heating is continued for 5.5 hours withoccasional supplement of benzene. After cooling, the reaction mixture ispoured onto 2 N sodium hydroxide solution (50 ml.). tracted withchloroform. The chloroform extract is combined with the benzene layer,washed with water, dried over anhydrous sodium sulfate and the solventremoved under reduced pressure. lized from a mixture of chloroform andether to give 3e hydroxy-20,20-ethylenedioxy-5a-pregnane-18-nitrile (3.0g.) as crystals melting at 189 to 191 C. r

The water layer is separated and ex- The residue (3.6 g.) is crystal- 7To a stirred suspension of lithium aluminum hydride (500 mg.) inanhydrous tetrahydrofuran (30 ml.), there is dropwise added a solutionof 3fi-hydroxy-20,20-ethylenedioxy-5a-pregnane-18-nitrile (345 mg.) inanhydrous tetrahydrofuran (10 ml.) in 5 minutes while cooling at C.After the addition is complete, the resultant mixture is refluxed for4.5 hours. The reaction mixture is combined with a mixture of ice andwater and extracted with chloroform. The chloroform extract is shakenwith 10% tartaric acid solution. The water layer is made alkaline withsolid sodium carbonate while cooling with ice and shaken withchloroform. The chloroform layer is washed with water, dried overanhydrous sodium sulfate and the solvent removed under reduced pressure.The residue (278.5 mg) is crystallized from a mixture of chloroform andether to give 3/3-hydroxy-l8-imino-20 20- ethylenediOXy-Sa-pregnane(245.9 mg.) as crystals melting at 185 to 201 C.

Example 14 To a solution ofSir-hydroxy-18-imino-20,20-ethylenedioxy-a-pregnane (213 mg.) intetrahydrofuran ml.) and methanol (10 ml.), there is added a mixture ofacetic acid (1.44 g.), sodium acetate (490 mg.) and water (4 ml.) whilecooling with ice, and the resultant mixture is refluxed for 5 minutes ona water bath. After cooling, the reaction mixture is combined with 10%potassium hydroxide solution and concentrated under reduced pressure.The residue is combined with a mixture of ice and water and shaken withchloroform. The chloroform layer is washed with 10% tartaric acidsolution, 2 N sodium carbonate and water in order, dried over anhydroussodium sulfate and the solvent evaporated under reduced pressure. Theresidue is crystallized from a mixture of chloroform and ether to give 38 hydroxy- 20,20-eth lenedioxy-5a-pregnan-18-al (199.3 mg.) as crystalsmelting at 186 to 192 C.

Example 1 5 A mixture of3fi-hydroxy-20,20-ethylenedioxy-Sa-pregnan-l8-al (147 mg.),triethyleneglycol (5 ml.), potassium hydroxide (260 mg.) and hydrazinehydrate (0.735 ml.) is gradually heated on an oil bath and heated at toC. for 30 minutes during which the eliminated water and excess of thehydrazine are distilled off. Then, the mixture is heated at 210 to 220C. for 3 hours. The reaction mixture is poured onto a mixture of ice andwater and shaken with chloroform. The chloroform layer is washed withwater, dried over anhydrous sodium sulfate and the solvent evaporated.The residue is crystallized from a mixture of acetone and ether to give-3fi-hydroxy- 20,20-ethylenedioxy-Su-pregnane (124.4 mg.) as crystalsmelting at 182 to 183 C.

Example 16 A solution of 3,B-hydroxy-Z0,20-ethylenedioxy-5ot-pregnane(97.5 mg.) in acetic acid (1.9 ml.) is heated on a water bath. Water(0.7 ml.) is added thereto. The resultant mixture is heated for 30minutes at 100 C. After evaporation of the solvent under reducedpressure, the residue is combined with a mixture of ice and water andshaken with chloroform. The chloroform layer is Washed with 2 N sodiumcarbonate solution and water in order, dried over anhydrous sodiumsulfate and the solvent evaporated under reduced pressure. Thecrystalline residue (92.4 mg.) is crystallized from a mixture of acetoneand ether to give 3fi-hydroxy-20-oxo-5a-pregnane (61.9 mg.) as crystalsmelting at 191 to 192 C.

What is claimed is:

1. 1,2,3,4,5,6,7,9,10,11a,l2fi,13ot dodecahydro 2,8- acyloxy 8(4,4-ethylenedioxypentyl)-l2fi-methyl-7-oxophenanthrene, acyloxy being amember selected from the group consisting of lower alkanoyloxy,benzoyloxy and alkylbenzoyloxy.

2. 1,2,3,4,5,6,7,9,10,11a,12}3,13oc dodecahydro 213-benzoyloxy-8-(4,4-ethylenedioxypentyl) 12 3 methyl-7- oxophenanthrene.

3. 1,2,3,4,5,6,7,9,10,1111,125,13oc dodecahydro 2/3- hydroxy8-(4,4-ethylenedioxypentyl) 1213 methyl-7- oxophenanthrene.

4. 1,2,3,4,5,6,7,8,9,10,11a,12fi3,13oc,14fltetradecahydro-2fl-hydroxy-8fl-(4,4-ethylenedioxypentyl)-12/3-methyl-7-oxophenanthrene.

5, 1,2,3,4 ,5,6,7,8,9,10,11oa,12fi,13oc,14fl tetradecahydro 2/3hydroxy-8p!-(4-oxopentyl)-12;3-methyl-7-oxophenanthrene.

6. 3fi-hydroxy-20-oxo-18-nor-5u-13(17)-pregnene.

7. 3fi-hydroxy 18 imino 20,20 ethyIenedioXy-Sapregnane.

8. 3B-hydroxy-20,20-ethylenedioxy-5u-pregnan-18-al.

References Cited by the Examiner UNITED STATES PATENTS 3,014,028 12/61Ruzicka et al. 260239.55 3,092,627 6/63 Wettstein et al 260-239.55

OTHER REFERENCES Nagata et al.: Tetrahedron Letter, No. 14, July 1963,pp. 865-868.

LEWIS GOTTS, Primary Examiner.

7. 3B-HYDROXY - 18 - IMINO - 20,20 - ETHYLENEDIOXY-5APREGNANE.